title: Clearance of rFVIIa and NN1731 after intravenous administration to Beagle dogs.
abstract: OBJECTIVE
  NN1731 is a recombinant activated factor VII (rFVIIa) analogue with enhanced activity. The objective of the present study was to evaluate the clearance mechanisms of rFVIIa and NN1731 after intravenous administration to Beagle dogs.
  
  
  METHODS
  The study was performed in Beagle dogs administered with a single dose of 5.4 nmol/kg rFVIIa or NN1731 intravenously. Plasma samples collected up to 12-h post-administration were analysed using three different assays to determine FVIIa clot activity (FVIIa:C), total FVIIa antigen, and levels of FVIIa-antithrombin (AT) complexes. Pharmacokinetic parameters were determined by use of standard non-compartmental and non-linear mixed effects methods.
  
  
  RESULTS
  For both compounds, complex formation with AT accounted for the observed difference between the activity and the antigen curves and constituted 60-70% of the total clearance. The clearance of rFVIIa and NN1731 was estimated to be 73 and 214 mL/h/kg, respectively, accordingly, AT complex formation occurred around three times faster for NN1731. The difference in activity observed in the initial phase, resulting in distribution half-lives of 0.71 and 0.22 h for rFVIIa and NN1731, was mainly caused by the 3-fold difference in clearance. The terminal half-life of rFVIIa and NN1731 was estimated to be 2.1 and 2.5 h, respectively. The non-compartmental analysis resulted in almost identical parameters.
  
  
  CONCLUSIONS
  The present study demonstrates that the difference between the activity and the antigen profiles of rFVIIa and NN1731 in Beagle dogs is the result of complex formation with AT which constitutes a major pathway for the clearance of rFVIIa activity.
authors.affiliation: Research and Development, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark. hkag@novonordisk.com
authors.forename: Henrik
authors.initials: H
authors.lastname: Agersø
authors.forename: Niels Rode
authors.initials: NR
authors.lastname: Kristensen
authors.forename: Henrik
authors.initials: H
authors.lastname: Østergaard
authors.forename: Ditte Maria
authors.initials: DM
authors.lastname: Karpf
authors.forename: Mette Brunsgaard
authors.initials: MB
authors.lastname: Hermit
authors.forename: Hermann
authors.initials: H
authors.lastname: Pelzer
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Petersen
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
mesh_terms: D000818:Animals; D058833:Antithrombin Proteins / Q000502:physiology; D001777:Blood Coagulation / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004285:Dogs; D005167:Factor VII / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D015942:Factor VIIa / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D058833:Antithrombin Proteins; C519901:NN1731; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa